EP2303838B1 - A new metformin glycinate salt for blood glucose control - Google Patents
A new metformin glycinate salt for blood glucose control Download PDFInfo
- Publication number
- EP2303838B1 EP2303838B1 EP08807218.6A EP08807218A EP2303838B1 EP 2303838 B1 EP2303838 B1 EP 2303838B1 EP 08807218 A EP08807218 A EP 08807218A EP 2303838 B1 EP2303838 B1 EP 2303838B1
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- EP
- European Patent Office
- Prior art keywords
- metformin
- salt
- ppm
- glycinate
- glycine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Not-in-force
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
Definitions
- This invention relates to the Metformin glycinate salt, which exhibits superior hypoglycaemic properties, greater bioavailability, a particular, safe pharmacokinetics.
- Metformin glycinate is a biguanide with pharmacological and pharmacokinetic properties different from those of metformin hydrochloride (generic medicament). Like the latter, glycinate metformin acts inhibiting hepatic glucose release and increasing peripheral sensitivity to endogenous insulin by promoting the fixation of insulin into its receptors, this is why it is considered an antihyperglycemic agent, since in this way prevents the increase of blood glucose levels.
- metformin hydrochloride metformin glycinate has shown to possess a hypoglycaemic effect in preclinical and clinical studies, decreasing the plasma glucose levels directly. The mechanism of action by which it causes this effect has not been defined yet, but it has been observed consistently in various studies.
- Metformin is a compound derived from biguanides that primarily acts by reducing hepatic gluconeogenesis, but also reduces glucose absorption at the gastro-intestinal tract level and increases sensitivity to insulin by increasing the peripheral utilisation of glucose. This may be due to the fact that Metformin improves the binding of insulin to its cellular receptor, which is explained by the increased activity that it induces in the tyrosine kinase postreceptor and the consequent increase in the number and activity of GLUT4 carriers.
- Metformin is not metabolized; it is directly excreted in the urine. Its half-life is 6.2 hours.
- Metformin and Metformin hydrochloride have poor intestinal absorption at the colon and the lower gastro-intestinal tract level.
- This invention relates to the development of a new biguanide salt based on Metformin conjugated with Glycine, which exhibits a better absorption and passage into the bloodstream, less gastro-intestinal adverse effects and a better pharmacokinetic profile as compared to other Metformin salts known in the prior art.
- Metformin hydrochloride is hygroscopic. This hinders the industrial handling thereof to prepare solid compositions such as tablets, capsules, etc. Moreover, in its solid form, it is a corrosive crystal, which wears the tabletting machines used. Furthermore, it is an extremely bitter salt for users and the acid generated thereby often causes gastric disorders with prolonged use.
- Patent GB 1473256 discloses, for the first time, biguanide salts for treating metabolic disorders, especially diabetes mellitus, by reducing blood glucose levels, with the following formula: where R 1 represents a hydrogen atom or a lower alkyl or a lower alkenyl group and R 2 represents a lower alkyl, aryl, aryl-(lower alkyl), or an aryloxy-(lower alkyl) group or R 1 and R 2 together represent a lower alkenyl group, R 3 represents a hydrogen atom or a group with the formula:
- R 4 and R 5 each represent a hydrogen atom or a cation or R 4 represents a hydrogen and R 5 represents a lower alkyl group, or R 4 and R 5 together represent a lower alkylene group, and n means 1 or 2.
- Metformin hydrochloride is the currently marketed salt and has the following formula:
- Belgian patent BE 568,513 discloses acid addition salts of Metformin, including Metformin hydrochloride.
- Patent application US 2005/0158374 discloses Metformin associated with fatty acids, with improved absorption at the gastro-intestinal tract level.
- This Metformin associated with a fatty acid (such as laureate, succinate, caprate, palmitate, etc.) is produced from a Metformin salt (for example, Metformin-HCl).
- Metformin salt for example, Metformin-HCl
- Metformin glycinate is particularly advantageous to reduce glycaemia, due to the high concentrations that it reaches in the first hour and which may be particularly useful in dealing with postprandial hyperglycaemia, which has been recognised as one of the main factors for cardiovascular risk and vascular damage.
- Metformin hydrochloride since it reaches higher maximum concentrations than Metformin hydrochloride, Metformin glycinate requires lower doses to produce similar hypoglycaemic effects.
- US 2008/031964 A1 and WO 2006/086856 A describe the combination of a betaine with an antidiabetic agent with the aim of increasing the efficacy of the said antidiabetic agent and diminish its side effects.
- the combination of Glycine-betaine (trimethylglycine) and powered metformin is used with a granulating agent in the form of spheres.
- WO 2005/065675 A refers either to betaine compounds in combination with metformin, the mixture intended to improve the metformin effects on body weight of the patient and long term glucose levels.
- Metformin Glycinate a new 1,1-dimethylbiguanide Glycinate salt was synthesised, called Metformin Glycinate.
- This salt exhibits advantages over other Metformin salts. These advantages are due, in the first place, to the fact that the glycine counterion exhibits hypoglycaemic effects by itself. Moreover, this salt exhibits more rapid absorption, reaching higher plasma concentrations than those produced with Metformin hydrochloride ( Figure 1 ). On the other hand, the glycine that is generated when the salt is ionised is not a strong acid; consequently, undesirable gastric effects are reduced. Finally, Metformin glycinate has favourable physical characteristics for industrial-scale handling, thus facilitating the preparation of pharmaceutical compositions, since it is less corrosive, has better rheological properties and is less susceptible to compacting.
- the salt produced was identified by means of nuclear magnetic resonance, infrared spectrometry, mass spectrometry and, finally, Monocrystal X-ray Diffraction. The analysis of the spectra indicated that the new salt produced is different from other Metformin compounds.
- the Nuclear Magnetic Resonance (RMN) proton spectrum showed displacements at 2,814 ppm, 2,916 ppm, 4,677 ppm.
- the infrared spectrum (IR) showed characteristic absorption signals at 3,367.34 cm-1, 3,175.88 cm-1, 1,618.78 cm-1, and 1,573.96 cm-1.
- compositions to be administered which may be in the form of a tablet, caplet, gel, paste, powder, prolonged-release granules, capsule, prolonged-release tablet, liquid with buffer agent, effervescent tablets, suspension, syrup, aerosol and others, or the administration route, which may be oral, intravenous injectable, intramuscular injectable, nasal, intraperitoneal, sublingual, etc.
- Metformin glycinate evaluated was not cytotoxic for any of the cell types used in this study in the two exposure periods evaluated (24 and 72 hours).
- the oral-route 50 Lethal Dose (LD 50 ) assay in Wistar rats was performed in compliance with international regulations and the specifications for the care and use of laboratory animals. The entire procedure was conceived as stipulated in Guideline 423 of the Guidelines of the Organisation for Economic Co-operation and Development.
- Randomisation 12 batches with 8 animals per batch. Four batches were used for the preliminary studies to find the dose interval and eight batches were used for the final study. Method: After fasting, different doses of the product were orally administered using an orogastric tube. During the development of the study, a control group was used in parallel.
- volume 3.8 ⁇ 0.4 ml (corresponding to a volume not greater than 2 ml for every 100 g of rat body weight). Observation period: 24 hours.
- the oral LD 50 obtained for Metformin glycinate 2.4625 ⁇ 0.195 g/kg.
- the LD 50 of Metformin hydrochloride is 1.45 g/kg.
- the OECD defines LD 50 as the "statistically derived single dose of a substance that can be expected to cause death in 50% of the laboratory animals.”
- the Subacute Toxicity test at 28 days was performed in compliance with international regulations and the specifications for the care and use of laboratory animals. Number of animals: 50 Wistar rats, young adults 3 months of age, of both sexes, were used. Five batches with ten animals each. Four experimental groups (10 animals in each group) and a control group. After fasting, different doses (low, medium, high, and satellite and control groups) of the product were orally administered using an orogastric tube.
- Observation Period 28 days. Satellite Group 15 days post-treatment (28 + 15). During the 28 days, the following studies were performed: Observation of the appearance of signs and symptoms, haematological tests and anatomic-pathological study. The entire procedure was conceived as stipulated in Guideline 407 of the Guidelines of the Organisation for Economic Co-operation and Development.
- the extrapolation of a probable dose to determine the non-observable adverse effect could be set between 0.5 and 1.0 g/kg.
- Metformin glycinate tablets equivalent to 850 mg of Metformin hydrochloride were administered to 12 healthy volunteers and were compared to the response of 12 other volunteers who received Metformin hydrochloride 850 mg.
- Samples were taken from the 24 volunteers in order to perform a pharmacokinetic curve, with the following resulting pharmacokinetic parameters: maximum concentration (C max ) 591 ng/ml, maximum time (t max ) 2.5 hours, area under the curve for 10 minutes at 24 hours (ABC( 10-24 )) 26.811 ⁇ g ⁇ ml/h, with a relative bioavailability of 2.8 ⁇ g/ml (see results in Figure 1 ).
- Metformin glycinate begins its biodegradation and its release during the first few minutes; consequently, there is rapid absorption, with the appearance of plasma levels between 0.00 and 0.13 h. These levels remain in circulation for over 10.00 hours.
- the circulating remnant (levels below 200 ⁇ g/ml) is present and tends to decrease within the next 12 hours and disappears when the drug is not administered the following morning.
- Metformin glycinate 1500 mg / kg base
- Metformin hydrochloride 1500 mg / kg base
- Glycine 871.6 mg/kg equivalent to glycine contained in the proven dose of Metformin glycinate
- Metformin base was selected to be close to lethal dosage.
- hypoglycemic effect was observed in the groups treated with metformin glycinate and metformin hydrochloride in both sexes, although it was much more pronounced in females.
- the glucose level decreased more in animals treated with the salt of the invention, metformin glycinate than in animals treated with metformin hydrochloride. This difference was statistically significant.
- the effect was maximal at 3 hours with both drugs, time in which there were decreases in glucose levels of 31% and 19% in males treated with metformin glycinate and Metformin hydrochloride; respectively, and 70% and 40 % in females respectively, taken as reference values recorded in the control group.
- metformin glycinate showed a more pronounced pharmacological effect on blood glucose and plasma lactate than metformin hydrochloride. The difference was more pronounced in females.
- glycine had no effect on blood glucose, suggesting that the most pronounced effect on glucose observed in the group treated with metformin glycinate is not due to an additive pharmacological effect of glycine: Deaths in this study were caused by a blood glucose lowering effect that was notoriously marked. At therapeutic doses, the effect was reproduced hipoglucemiente in clinical trials, where it was also observed a reduction in glycated hemoglobin of 1%.
- Metformin glycinate of the invention has pharmacological and pharmacokinetic properties than the metformin hydrochloride (generic medicament). This means that at salt cannot, be considered a bioequivalent salt and therefore studies reported here characterize its pharmacodynamic activity, its pharmacokinetic profile and safety profile. Preclinical and clinical studies show differences with respect to metformin hydrochloride.
- the salt of the invention, metformin glycinate has shown a different pharmacological activity with respect to the hydrochloride salt in regard to the hypoglycemic activity. This difference has been shown in preclinical and clinical trials. It has also been shown to have a different pharmacokinetic profile in humans.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL08807218T PL2303838T3 (pl) | 2008-06-26 | 2008-06-26 | Nowa sól glicynianowa metforminy do kontroli glukozy we krwi |
SI200831163T SI2303838T1 (sl) | 2008-06-26 | 2008-06-26 | Nova sol metformin glicinata za nadzor glukoze v krvi |
CY20141100150T CY1115098T1 (el) | 2008-06-26 | 2014-02-25 | Νεο γλυκινικο αλας μετφορμινης για ελεγχο γλυκοζης αιματος |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB2008/002665 WO2009144527A1 (en) | 2008-06-26 | 2008-06-26 | A new metformin glycinate salt for blood glucose control |
Publications (2)
Publication Number | Publication Date |
---|---|
EP2303838A1 EP2303838A1 (en) | 2011-04-06 |
EP2303838B1 true EP2303838B1 (en) | 2013-12-04 |
Family
ID=40383805
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08807218.6A Not-in-force EP2303838B1 (en) | 2008-06-26 | 2008-06-26 | A new metformin glycinate salt for blood glucose control |
Country Status (26)
Country | Link |
---|---|
US (2) | US8703183B2 (pl) |
EP (1) | EP2303838B1 (pl) |
JP (1) | JP5551691B2 (pl) |
KR (1) | KR101522066B1 (pl) |
CN (1) | CN102159539B (pl) |
AR (1) | AR074159A1 (pl) |
AU (1) | AU2008357111B2 (pl) |
BR (1) | BRPI0822909B8 (pl) |
CA (1) | CA2729035C (pl) |
CL (1) | CL2009001484A1 (pl) |
CY (1) | CY1115098T1 (pl) |
DK (1) | DK2303838T3 (pl) |
EC (1) | ECSP10010719A (pl) |
ES (1) | ES2450148T3 (pl) |
HR (1) | HRP20140194T1 (pl) |
JO (1) | JO2884B1 (pl) |
MA (1) | MA32418B1 (pl) |
MX (1) | MX2011000135A (pl) |
NI (1) | NI201000234A (pl) |
PE (1) | PE20100257A1 (pl) |
PL (1) | PL2303838T3 (pl) |
PT (1) | PT2303838E (pl) |
SI (1) | SI2303838T1 (pl) |
TN (2) | TN2010000607A1 (pl) |
UY (1) | UY31945A (pl) |
WO (1) | WO2009144527A1 (pl) |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MX2011000135A (es) | 2008-06-26 | 2011-02-25 | Silanes Sa De Cv Lab | Una nueva sal de glicinato de metformina para el control de la glucosa en sangre. |
US8765811B2 (en) | 2012-07-10 | 2014-07-01 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US9382187B2 (en) | 2012-07-10 | 2016-07-05 | Thetis Pharmaceuticals Llc | Tri-salt form of metformin |
US9171343B1 (en) | 2012-09-11 | 2015-10-27 | Aseko, Inc. | Means and method for improved glycemic control for diabetic patients |
US9897565B1 (en) | 2012-09-11 | 2018-02-20 | Aseko, Inc. | System and method for optimizing insulin dosages for diabetic subjects |
CN103263405B (zh) * | 2013-05-08 | 2015-04-22 | 南京医科大学 | 用于治疗糖尿病的药物组合物及其应用 |
US9815777B2 (en) | 2013-09-22 | 2017-11-14 | Jiva Pharma, Inc. | Metformin salts to treat Type2 diabetes |
US9898585B2 (en) | 2014-01-31 | 2018-02-20 | Aseko, Inc. | Method and system for insulin management |
US9486580B2 (en) | 2014-01-31 | 2016-11-08 | Aseko, Inc. | Insulin management |
WO2015171516A1 (en) | 2014-05-05 | 2015-11-12 | Thetis Pharmaceuticals Llc | Compositions and methods relating to ionic salts of peptides |
WO2015183794A1 (en) * | 2014-05-27 | 2015-12-03 | City Of Hope | Tgr5 agonist complexes for treating diabetes and cancer |
US9242008B2 (en) | 2014-06-18 | 2016-01-26 | Thetis Pharmaceuticals Llc | Mineral amino-acid complexes of fatty acids |
CN107074884A (zh) | 2014-06-18 | 2017-08-18 | 西蒂斯制药有限责任公司 | 活性剂的矿物质氨基酸复合物 |
US11081226B2 (en) | 2014-10-27 | 2021-08-03 | Aseko, Inc. | Method and controller for administering recommended insulin dosages to a patient |
AU2015339576B2 (en) | 2014-10-27 | 2020-02-06 | Glytec, Llc | Subcutaneous outpatient management |
CN105030745A (zh) * | 2015-07-08 | 2015-11-11 | 南京医科大学 | 甘氨酸和二甲双胍的酰胺化产物在制备治疗糖尿病药物中的应用 |
AU2016308953B2 (en) | 2015-08-20 | 2020-09-10 | Glytec, Llc | Diabetes management therapy advisor |
CA3026264A1 (en) | 2016-06-03 | 2017-12-07 | Thetis Pharmaceuticals Llc | Compositions and methods relating to salts of specialized pro-resolving mediators |
BR112019006401A2 (pt) * | 2016-09-30 | 2019-06-25 | Laboratorios Silanes S A De C V | glicinato de metformina, composições farmacêuticas que compreendem o mesmo e métodos de uso do mesmo |
US11510886B2 (en) | 2016-09-30 | 2022-11-29 | Laboratorios Silanes, S.A. De C.V. | Metformin amino acid compounds and methods of using the same |
CN113105367B (zh) * | 2021-03-30 | 2022-08-02 | 广州大学 | 一类二甲双胍盐及其制备方法和应用 |
CN114349665B (zh) * | 2021-11-30 | 2023-06-09 | 潍坊博创国际生物医药研究院 | 二甲双胍焦谷氨酸晶体及其制备方法与应用 |
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BE568513A (pl) | ||||
FR2037002A1 (en) | 1969-04-30 | 1970-12-31 | Roques Bernard | N-substd biguanide pamoic acid salts prepn |
DE1967138A1 (de) | 1969-07-17 | 1977-11-10 | Christian Brunnengraeber Chem | Therapeutisches mittel |
AT325632B (de) | 1973-06-01 | 1975-10-27 | Hurka Wilhelm | Verfahren zur herstellung von nicotinsauren salzen von derivaten des biguanids |
FR2243684B1 (pl) | 1973-09-19 | 1977-01-28 | Semb | |
CH602612A5 (pl) | 1974-10-11 | 1978-07-31 | Hoffmann La Roche | |
FR2320735A1 (fr) | 1975-08-12 | 1977-03-11 | Dabis Georges | Composition anti-cellulite |
JPS57179494A (en) | 1981-04-30 | 1982-11-05 | Mitsubishi Plastics Ind | Method of closing through hole of pipe, circumferential wall thereof has through hole in pipe axial direction |
FR2585572B3 (fr) | 1985-07-31 | 1987-12-31 | Hugelin Andre | Nouvelles compositions pharmaceutiques a base d'un sel de l'acide p. chlorophenoxyacetique destinees au traitement des neuropathies et assurant la regeneration nerveuse |
DE793646T1 (de) * | 1994-11-23 | 1999-12-30 | Pharmacia & Upjohn Co., Kalamazoo | Carboxylierte aminoguanidine zum behandlung von insulin-unabhängigem diabetes mellitus |
WO1999029314A1 (en) | 1997-12-08 | 1999-06-17 | Bristol-Myers Squibb Company | Novel salts of metformin and method |
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WO2007149313A1 (en) * | 2006-06-16 | 2007-12-27 | Indigene Pharmaceuticals Inc. | Metformin r-(+) lipoate as an antidiabetic agent for control of diabetic hyperglycemia and diabetic complications |
NZ556735A (en) * | 2007-07-24 | 2009-03-31 | Vector Ltd | Securing devices and equipotential bonding system |
MX2011000135A (es) | 2008-06-26 | 2011-02-25 | Silanes Sa De Cv Lab | Una nueva sal de glicinato de metformina para el control de la glucosa en sangre. |
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2008
- 2008-06-26 MX MX2011000135A patent/MX2011000135A/es active IP Right Grant
- 2008-06-26 JP JP2011515639A patent/JP5551691B2/ja not_active Expired - Fee Related
- 2008-06-26 SI SI200831163T patent/SI2303838T1/sl unknown
- 2008-06-26 ES ES08807218.6T patent/ES2450148T3/es active Active
- 2008-06-26 PT PT88072186T patent/PT2303838E/pt unknown
- 2008-06-26 CN CN200880130084.3A patent/CN102159539B/zh active Active
- 2008-06-26 EP EP08807218.6A patent/EP2303838B1/en not_active Not-in-force
- 2008-06-26 BR BRPI0822909A patent/BRPI0822909B8/pt active IP Right Grant
- 2008-06-26 DK DK08807218.6T patent/DK2303838T3/en active
- 2008-06-26 AU AU2008357111A patent/AU2008357111B2/en not_active Ceased
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- 2008-06-26 WO PCT/IB2008/002665 patent/WO2009144527A1/en active Application Filing
- 2008-06-26 CA CA2729035A patent/CA2729035C/en not_active Expired - Fee Related
- 2008-06-26 KR KR1020117000071A patent/KR101522066B1/ko active IP Right Grant
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2009
- 2009-06-25 PE PE2009000908A patent/PE20100257A1/es active IP Right Grant
- 2009-06-25 JO JO2009233A patent/JO2884B1/en active
- 2009-06-25 CL CL2009001484A patent/CL2009001484A1/es unknown
- 2009-06-26 AR ARP090102388A patent/AR074159A1/es unknown
- 2009-06-26 UY UY0001031945A patent/UY31945A/es not_active Application Discontinuation
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2010
- 2010-12-23 NI NI201000234A patent/NI201000234A/es unknown
- 2010-12-24 EC EC2010010719A patent/ECSP10010719A/es unknown
- 2010-12-24 US US12/928,985 patent/US8703183B2/en not_active Ceased
- 2010-12-27 TN TNP2010000607A patent/TN2010000607A1/fr unknown
- 2010-12-27 MA MA33460A patent/MA32418B1/fr unknown
- 2010-12-27 TN TNP2010000604A patent/TN2010000604A1/fr unknown
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2014
- 2014-02-25 CY CY20141100150T patent/CY1115098T1/el unknown
- 2014-03-03 HR HRP20140194AT patent/HRP20140194T1/hr unknown
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2016
- 2016-04-21 US US15/135,018 patent/USRE46496E1/en active Active
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